Acute COVID-19 Cardiovascular Syndrome

10.1161/CIRCULATIONAHA.120.047349

Description and Proposed Management of the Acute COVID-19

Cardiovascular Syndrome

Running Title: Hendren et al.; Acute COVID-19 Cardiovascular Syndrome

Nicholas S. Hendren, MD1; Mark H. Drazner, MD, MSc1; Biykem Bozkurt, MD, PhD2;

Leslie T. Cooper, Jr., MD3

1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas,

TX; 2 Winters Center for Heart Failure Research, Cardiovascular Research Institute,

Downloaded from http://ahajournals.org by on April 17, 2020 Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX;

3Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL

Address for Correspondence: Leslie T. Cooper, Jr., MD Department of Cardiovascular Medicine, Mayo Clinic 4500 San Pablo Road Jacksonville, FL 32224 Tel: 904-953-6351 Fax: 904-953-2911 E-mail: [email protected].

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Abstract

Coronavirus Disease 2019 (COVID-19) is a rapidly expanding global pandemic due to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an Acute COVID-19 Cardiovascular Syndrome (ACovCS) that can manifest with a variety of clinical presentations, but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias and hemodynamic instability in the absence of obstructive coronary artery disease. The etiology of this injury is uncertain, but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury or stress-related cardiomyopathy. Although histologically unproven, SARS-CoV-2 has the potential to directly replicate within cardiomyocytes and pericytes leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) has helped expedite the evaluation of several promising therapies including anti-viral agents, interleukin-6 inhibitors, and convalescent serum. Management of ACovCS should involve a multidisciplinary team including intensive care specialists, infectious disease specialists and cardiologists. Priorities for managing ACovCS include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point where intervention may be most effective. The aim of this paper is to review the best available data on ACovCS epidemiology, pathogenesis, diagnosis and treatment. From these data, we propose a surveillance, diagnostic and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.

Downloaded from http://ahajournals.org by on April 17, 2020 Key Words: coronavirus disease 2019; myocarditis; stress-induced cardiomyopathy

Non-standard Abbreviations and Acronyms ACE2 angiotensin-converting enzyme 2 ACovCS acute COVID-19 cardiovascular syndrome CAR-T chimeric antigen receptor T COVID-19 coronavirus disease 2019 cMRI cardiac magnetic resonance imaging CRS cytokine release syndrome CT computed tomography DIC disseminated intravascular coagulopathy cTnI cardiac troponin I ECMO extracorporeal membrane oxygenation EKG electrocardiogram GDMT guideline-directed medical therapy hs-cTnI high-sensitivity cardiac troponin I IL-6 interleukin 6 IVIG intravenous immunoglobulin LVEF left ventricular systolic function MERS Middle Eastern respiratory syndrome S spike SARS severe acute respiratory syndrome

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SARS-CoV-1 severe acute respiratory syndrome coronavirus-1 SARS-CoV-2 severe acute respiratory syndrome coronavirus-2 TMPRSS2 transmembrane serine protease 2 Downloaded from http://ahajournals.org by on April 17, 2020

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Introduction

Since the index cases were first reported in Wuhan, China in December 2019, Coronavirus

Disease 2019 (COVID-19) due to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-

CoV-2) has become a global pandemic infecting >1 million individuals by early April, 2020 1, 2.

In addition to systemic and respiratory complications, COVID-19 can manifest with an acute

cardiovascular syndrome (what we have termed ‘ACovCS’, see Table 1 & Figure 1). In this

document, we focus on a prominent myocarditis-like syndrome involving acute myocardial

injury often associated with reduced left ventricular ejection fraction in the absence of

obstructive coronary artery disease. This syndrome can be complicated by cardiac arrhythmias

and/or clinical heart failure with or without associated hemodynamic instability including shock

1, 3. These cardiac complications can occur precipitously at any point during hospitalization and

are increasingly being described as a late complication that can occur after improvements in a Downloaded from http://ahajournals.org by on April 17, 2020 patient’s respiratory status 4, 5. ACovCS may be due to acute coronary syndrome, demand

ischemia, microvascular ischemic injury, injury related to cytokine dysregulation or myocarditis

6, 7. The aim of this paper is to review the available data on ACovCS epidemiology, pathogenesis,

diagnosis and treatment. From these data we propose a surveillance, diagnostic and management

strategy that balances patient and health care provider risks with potential improvement in

meaningful clinical outcomes.

Myocardial Injury in Patients with COVID-19

Acute myocardial damage during a viral illness may be inferred from rises in specific

biomarkers, characteristic electrocardiogram (EKG) changes and/or new imaging features of

impaired cardiac function. Prior experiences from Middle Eastern Respiratory Syndrome

(MERS), Severe Acute Respiratory Syndrome (SARS), COVID-19 and non-SARS

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coronaviruses demonstrate that coronavirus can cause acute myocarditis 7-12. In COVID-19, the

frequency and differential patterns of troponin release in the context of a clinical presentation of

a type 1 or 2 myocardial infarction, myocarditis or cytokine/stress related cardiomyopathy is not

well defined. Anecdotal reports have described cases of acute myocardial injury characterized by

marked cardiac troponin elevation accompanied by ST-segment elevation or depression on EKG,

and angiography often without epicardial coronary artery disease or culprit lesions identified 11,

13. These early data suggest that the dominant cause of myocardial injury for this phenotype is

myocardial injury in the absence of epicardial coronary artery thrombosis. Additionally,

myocarditis, systemic cytokine-mediated, stress-related cardiomyopathy, or microvascular

thrombosis could produce an acute myocardial injury pattern (Figure 2).

Acute myocardial injury as assessed by troponin release alone appears to complicate a

substantial minority of hospitalized patients with COVID-19, particularly patients that require Downloaded from http://ahajournals.org by on April 17, 2020 intensive care. Analysis of a series of 52 critically ill patients in China with COVID-19 revealed

myocardial injury (high-sensitivity cardiac troponin I [hs-cTnI] >28 ng/L) in 29% of patients 14.

Analysis of a second Chinese single center retrospective report of 416 patients hospitalized with

COVID-19 observed approximately 20% (82/416) of patients had an acute myocardial injury

(cardiac troponin I [cTnI] >0.04 µg/L) and patients with myocardial injury were older and had a

higher burden of comorbid disease 15. Myocardial injury was associated with a higher observed

mortality that persisted after adjustment for baseline characteristics and medical comorbidities 15.

A report from a another Chinese multicenter retrospective study comprising data from 191

patients hospitalized with COVID-19 observed myocardial injury (cTnI >28 ng/L) in 1/95 (1%)

of surviving patients compared with 32/54 (59%) of patients who did not survive 16. Lastly,

results from a meta-analysis revealed abnormal cTnI values (>99th percentile) in 8-12% of

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patients hospitalized in COVID-19 and elevations were associated with more severe

complications and worse outcomes 17. The mean difference in cTnI value was 25.6 ng/L (95% CI

6.8–44.5 ng/L) between those with (n=123) and without (n=218) severe disease 17. Although the

troponin samples were not systematically collected and their ascertainment may be influenced by

indication bias, these data are supportive that acute myocardial injury is commonly observed in

COVID-19 and is prognostic for worse outcomes.

The mechanism of acute myocardial injury in COVID-19 is unresolved. Several cases of

clinically diagnosed myocarditis relating to COVID-19 (without histology or pathology, but with

supporting imaging) have been reported, including one case requiring veno-arterial

extracorporeal membrane oxygenation (ECMO) 11, 18, 19. The patient treated with ECMO was also

treated with steroids, intravenous immunoglobulins and anti-viral therapy, and subsequently

recovered 19. In a case series of 150 patients, 5/68 (7%) of reported deaths reported acute Downloaded from http://ahajournals.org by on April 17, 2020 myocardial injury with heart failure and another 22/68 (32%) deaths reported acute myocardial

injury with heart failure as contributing factor 20. Limited autopsy and endomyocardial biopsy

results have been reported, but a case report from Italy has described biopsy-proven acute

lymphocytic myocarditis in an individual with COVID-19 7. A second case report described a

patient with COVID-19 presenting with acute myocardial injury and cardiogenic shock 12. The

patient underwent an endomyocardial biopsy which demonstrated low‐grade myocardial

inflammation and the absence of myocyte necrosis with localization of SARS-CoV-2 within

macrophages, but not cardiomyocytes 12. This case confirms that SARS-CoV-2 can reside within

the heart, but does not provide evidence for cardiotropic viral cell entry. Altogether, these studies

confirm that acute myocarditis is a mechanism of myocardial injury in some patients with

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COVID-19, although the proportion of myocardial injury related to acute lymphocytic

myocarditis remains uncertain.

Additional reports from Wuhan indicate a significant proportion of non-surviving patients

also had elevated transaminases, lactate dehydrogenase, creatine kinase, d-dimer, serum ferritin,

interleukin 6 (IL-6) and prothrombin time, which in totality suggest markedly elevated pro-

inflammatory mediators and a cytokine profile similar to the cytokine release syndrome 15, 16.

This constellation of inflammatory cytokines has inherent similarities to chimeric antigen

receptor T (CAR-T) induced cytokine release syndrome (CRS) which results in marked

elevations of IL-6, and interferon-γ 21. For ACovCS, it is unclear to what extent such cytokine

elevations cause or contribute to myocardial injury, left ventricular dysfunction and cardiac

troponin elevation. Additional studies, including collection of endomyocardial tissue by biopsy

and autopsy studies, will be required to delineate the pattern and proportion of ACovCS related Downloaded from http://ahajournals.org by on April 17, 2020 to acute myocarditis versus general myocardial injury due to systemic cytokine dysregulation.

COVID Target Tissues

The majority of prior experience with myocardial injury associated with viral infections is

gleaned from data deriving from infections not related to coronaviruses. For example, clinical

syndromes with COVID-19 suggest a higher prevalence of myocardial injury compared with that

observed with wild-type coxsackie virus infections. The outbreak of SARS-CoV-1 in 2003, the

SARs pandemic, resulted in investigations that have the potential to inform our understanding of

SARS-CoV-2. Investigation into SARS-CoV-1 revealed that the virus expresses numerous spike

(S) proteins on the surface of the viral envelope that are vital to the transmission of infection

(Figure 3) 22. These S proteins bind via the S1 subunit to angiotensin-converting enzyme 2

(ACE2) expressed on host cells, but merely binding to ACE2 is not sufficient for cell infection

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22. Viral cell entry requires the transmembrane serine protease 2 (TMPRSS2) expressed on host

cells to perform critical protein priming that leads to conformational changes, viral cell entry and

cell infection 22, 23. Investigation into SARS-CoV-2 has confirmed the importance of the S1

protein binding to ACE2 on target cells and the expression of the TMPRSS2 protease for host

cell infection 24.

Mechanisms that disrupt the S1 subunit binding, ACE2 binding or TMPRSS2 protease

activity pose potential therapeutic targets. This theory was tested with the evaluation of the effect

of antibodies to the S protein obtained from the convalescent serum of SARS-CoV-2 patients.

Antibody administration reduced viral cell entry in a concentration-dependent manner

demonstrating partial successful inhibition of viral entry in an in vitro cell line 24. Furthermore,

the administration of anti-ACE2 antibodies has been demonstrated to inhibit SARS-CoV-1 and

SARS-CoV-2 viral replication in an in vitro cell preparation in a dose dependent fashion further Downloaded from http://ahajournals.org by on April 17, 2020 supporting the importance of the receptor as necessary for cellular entry 22, 24. Additionally,

results from early pre-clinical studies using recombinant ACE2 administration report effectively

neutralizing SARS-CoV-1 and SARS-CoV-2 in vitro 25. Lastly, inhibitors of the serine protease

TMPRSS2 were effective in reducing cellular entry for both SARS-CoV-1 and SARS-CoV-2 in

an in vitro model 24. These studies clarify the mechanism of viral cell entry and highlight three

distinct potential therapeutic targets that are theorized to reduce cellular entry and pathogenesis.

The results from these small in vitro studies suggest anti-ACE2, TMPRSS2 inhibitors and

inhibitors of S1 protein subunits may reduce viral propagation in host cells, although further

study is required.

Given the essential nature of ACE2 for viral infection, the distribution of ACE2

expression is informative to elucidate the likely infected tissues and hypothetical mechanisms of

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injury. ACE2 is prominently found in type 1 and II lung alveolar epithelium, pericytes,

cardiomyocytes, enterocytes in the small intestine including the duodenum, jejunum, and ileum,

and arterial and venous endothelial cells 26-28. Autopsy studies in patients deceased due to SARS-

CoV-1 have confirmed the presence of virus within cells that prominently express ACE2

including bronchiolar and alveolar epithelial cells, renal tubular epithelial cells, mucosal and

crypt epithelial cells of the gastrointestinal tract, and cardiomyocytes 29. Analyses of histologic

samples of pulmonary tissue in patients with COVID-19 reveal a similar pattern of injury as was

reported with SARS-CoV-1 30. Although these data are extremely limited for COVID-19 at this

juncture, they offer proof of concept of direct cellular injury in tissues with ACE2 expression.

The myocardial cellular targets for SARS-CoV-2 may include pericytes, cardiomyocytes,

fibroblasts, and immune cells such as resident macrophages.

Myocardial Pathology Downloaded from http://ahajournals.org by on April 17, 2020 Pathological examination may help clarify whether myocardial injury predominately occurs

indirectly due to systemic cytokines or directly due to viral cardiomyocyte infection or some

other mechanism. Acute cellular injury due to SARS-COV-2 cardiomyocyte, pericyte or

fibroblast infection via ACE2-mediated entry and subsequent viral replication is a theoretical but

unproven process. Analyses of histologic specimens have demonstrated direct cellular viral

infection of the myocardium and cells within the conduction pathways of the heart with SARS-

CoV-1 29, 31, 32. Prior acute myocarditis experience with alternative viruses suggests direct

cellular injury is related to a combination of cardiotropic viral entry into myocytes and the

subsequent innate immune response that can lead to focal or diffuse myocardial necrosis 33.

Within a few days of this direct cellular injury, edema and necrosis can lead to contractile

dysfunction and clinical symptoms 33. If true in COVID-19, this delayed injury could potentially

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manifest as an abrupt clinical decline after several days of stability. Cardiotropic viruses, such as

SARS-CoV-1, are typically cleared from the myocardium within 5 days; however, infrequently

the virus may persist in the myocardium for several weeks to months 34. Presuming SARS-CoV-

2 can directly infect the myocardium, any associated myocarditis will predominately be manifest

in the acute or subacute stage. It is also uncertain if SARS-CoV-1 or SARS-CoV-2 leads to the

production of cardiac auto-antibodies that develop due to molecular mimicry, as previously

demonstrated between Coxsackie B virus proteins and the S2 regions of cardiac myosin 35.

Whether viral persistence or inflammation from COVID-19 can cause a chronic dilated

cardiomyopathy as occurs after coxsackie B virus myocarditis is also unknown.

Alternatively, myocardial injury in COVID-19 may also result from profound

inflammatory activation and cytokine release 16. Analysis of a small case series of minimally

invasive autopsy in three patients deceased from COVID-19 described the presence SARS-CoV- Downloaded from http://ahajournals.org by on April 17, 2020 2 within alveolar tissue 36. SARS-CoV-2 was not isolated from cardiac tissue, but degenerative

changes and necrosis suggested a secondary mechanism of injury 36. These preliminary

observations raise the possibility that SARS-CoV-2, unlike SARS-CoV-1 as described above,

may not directly cause cellular injury. Indeed, acute myocardial injury in the setting of non-

COVID-19 viral immune activation can result from immune-mediated injury due to activated T

and B cells leading to an inflammatory cascade, cytokine production and antibody production 33,

37. Further studies in stress-induced and non-COVID-19 viral associated cardiomyopathy have

associated increased levels of cytokines with myocardial injury 38, 39. As discussed, a profound

inflammatory response with marked cytokine production commonly occurs in hospitalized

patients with severe or critical COVID-19 16. This marked inflammatory response can also lead

to the development of disseminated intravascular coagulopathy (DIC) in critically ill patients. In

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183 consecutive Chinese patients admitted with COVID-19, coagulopathy was associated with

higher mortality and 15/21 (71%) of non-surviving patients met criteria for DIC 40. Localized

pulmonary arteriolar thrombosis was described in SARS and pulmonary emboli have been

reported in COVID-19 41. As such, microvascular thrombosis in coronary vessels due to DIC is

another potential but unproven mechanism that may contribute to myocardial injury 42.

In short, SARS-CoV-2 has the potential to infect cardiomyocytes, pericytes and

fibroblasts via the ACE2 pathway leading to direct myocardial injury, but that

pathophysiological sequence remains unproven. A second hypothesis to explain COVID-19

related myocardial injury centers on cytokine excess and/or antibody mediated mechanisms.

Further investigation via autopsy and endomyocardial biopsy tissue will be needed to clarify

which of these is the predominate mechanism of injury in ACovCS.

Historical Outcomes Downloaded from http://ahajournals.org by on April 17, 2020 Patients with acute viral myocarditis commonly present following a viral syndrome with clinical

heart failure, chest pain, abnormal electrocardiograms that can mimic an acute coronary

syndrome, and/or ventricular arrhythmias 43, 44. This constellation of findings is increasingly

being described in patients infected with COVID-19, raising suspicion for acute viral associated

injury from a myocarditis-like presentation 6. There is a paucity of published data on the cardiac

complications of MERS and SARS. Patients with pre-existing cardiovascular disease have

increased mortality observed for both SARS and COVID-19; however, cardiac complications

appear to be less prevalent in SARS compared with COVID-19 16, 45.

Diagnosis

Historically, patients are typically diagnosed with acute myocarditis if they have <30 days of

symptoms with an abnormal troponin and cardiac magnetic resonance imaging (cMRI) findings

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meeting the revised Lake Louise 2018 criteria 46, 47. In non-COVID-19 cases, endomyocardial

biopsy has been traditionally recommended in fulminant presentations to exclude the rare

presentation of eosinophilic, hypersensitive, and giant-cell myocarditis 48. However, in the

setting of COVID-19, such an approach may not be feasible due to instability of the patient,

procedural risk and risk of healthcare staff exposure, especially if the biopsy results would not

change clinical management. Patterns of delayed myocardial enhancement consistent with acute

myocarditis have also been described in contrast-enhanced EKG-gated multidetector computed

tomography (CT) in non-COVID-19 cases 49, 50. This may be a useful rapid and noninvasive

diagnostic test to assess for myocardial injury in COVID-19 patients who complete a CT-scan

for non-cardiac reasons and represents an opportunity for investigation.

Given the extremely contagious and morbid nature of COVID-19, the priorities related to

managing and diagnostic options for a patient with ACovCS include reducing staff/patient Downloaded from http://ahajournals.org by on April 17, 2020 exposures, a goal that can be facilitated by limiting testing and patient transfer for diagnostic

procedures, especially those that do not directly influence patient management. Another

consideration is to limit testing that requires terminal room cleaning required by patient transfer,

as that process can add significant delays to diagnostic testing for other patients. Such strategies

may result in increased uncertainty about the diagnosis, but are unlikely to increase adverse

short-term outcomes in patients without fulminant presentations. For example, for patients noted

to have acutely elevated troponin, if a type 1 myocardial infarction can be excluded on clinical

grounds, then a biopsy is unlikely to change immediate clinical management whether the clinical

syndrome is due to myocarditis, cytokine-induced myocardial injury, or a type 2 myocardial

infarction. As such, routine endomyocardial biopsy in patients with active COVID-19 with

abnormal cardiac biomarkers, regardless of fulminant or non-fulminant presentation, is

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discouraged. This strategy is aligned with recent American College of Cardiology

recommendations 51. However, an exception to that approach could be a COVID-19 patient with

hemodynamic and/or electrophysiologic instability who undergo coronary angiography to

exclude obstructive coronary artery disease. In that setting, the patient is already in the

catheterization laboratory so the incremental infectious risk is reduced since additional transport

is not needed; such opportunities may be useful to gain insights into the mechanism of the acute

myocardial injury, including the possibility of giant cell myocarditis which presumably can still

occur during the COVID-19 pandemic.

In accordance with these guiding principles, the majority of patients with an abnormal

troponin in the setting of COVID-19 infection can be followed with expectant management until

recovery from the acute viral syndrome. Extrapolating from prior experiences, patients with

COVID-19 and myocardial injury whom are hemodynamically and electrophysiologically stable Downloaded from http://ahajournals.org by on April 17, 2020 with mild-moderate elevations of troponin should not routinely undergo an echocardiogram,

angiography or cardiac imaging. These diagnostic studies likely can be avoided altogether, or

delayed until recovery from COVID-19 unless the patient clinically deteriorates and develops

hemodynamic instability, shock, ventricular arrhythmias or a severely elevated or rapidly rising

troponin (Figure 4). However, if the treating clinician has the ability to perform point-of-care

cardiac ultrasonography without increasing COVID-19 exposure, this would be reasonable to

perform, as a low ejection fraction would identify higher-risk patients and support earlier

initiation of guideline directed medical therapy once the patient is stable. However, unnecessary

or repeated imaging not vital to clinical decision-making should be avoided in accordance with

the American Society of Echocardiography COVID-19 statement 52. Patients discovered to have

newly diagnosed depressed left ventricular systolic function (LVEF) without troponin elevated

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are more likely to have pre-existing cardiomyopathy than myocarditis. While the lack of

definitive diagnostic studies may temporarily increase diagnostic uncertainty, it reduces the risk

of COVID-19 transmission to staff and in clinically stable patients seems less likely to

compromise short term (<60 day) patient outcomes.

Historical Treatments for SARS

Similar to COVID-19, SARS presented with a spectrum of symptoms and the majority of

patients only required supportive care 53. Several antiviral agents were used empirically in

patients with severe respiratory compromise including ribavirin 53. Ribavirin for SARS was

eventually abandoned due to a lack of antiviral activity against SARS-CoV-1 and lack of

efficacy in clinical trials 54, 55.

Like COVID-19, patients with SARS developed progressive respiratory failure despite

declining viral loads and rising antibody concentrations, a deterioration theorized to be an Downloaded from http://ahajournals.org by on April 17, 2020 immune-mediated injury related either antibodies or elevated cytokine levels 53, 56, 57. Steroid

protocols were developed ranging from intravenous hydrocortisone 2 mg/kg four times daily to

intravenous methylprednisolone 500 mg daily for five days with various taper protocols 53.

Steroid treatment for SARS yielded inconsistent benefit with some studies associating steroids

with increased mortality and higher rate of intensive care, while others suggested modest

radiographic or oxygen improvements 53. A postmortem series of patients detected high viral

loads in patients up to 30 days after illness onset, possibly because corticosteroids prolonged the

duration of viral replication 58. Additional therapies including tumor necrosis factor alpha-

blockers, and convalescent plasma with anti-SARS-CoV-1 antibodies were proposed, but not

rigorously studied. Although a concern, acute myocardial injury including myocarditis appeared

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uncommon and there was scant published guidance for the management of SARS-CoV-1

myocardial injury.

Treatment of Acute COVID-19 Cardiovascular Syndrome

There are no comprehensive expert recommendations and limited data from high quality studies

to inform our clinical decision making for the pharmacotherapy of ACovCS. Since most small

case series and studies of viral myocarditis in general involve fulminant and otherwise

complicated presentations, there is significant publication bias in the literature. Published

experiences of COVID-19 associated myocardial injury is even more limited, including

retrospective small case series and/or individual case reports. As such, the best practices for

treating the acute myocardial injury in ACovCS currently need to be extrapolated from prior

non-COVID-19 experiences and the available, limited quality COVID-19 data. In general,

treatment of ACovCS should be completed with a multidisciplinary team including infectious Downloaded from http://ahajournals.org by on April 17, 2020 disease consultation to help guide therapy selection. Several experimental therapies attempting to

limit SARS-CoV-2 replication or the immune response have been proposed with multiple

clinical trials currently underway. Currently there are no therapies with rigorous clinically

supported efficacy for COVID-19 in general, or specifically for ACovCS. If possible, enrollment

in on-going clinical trials is encouraged.

Hydroxychloroquine is a proposed treatment for COVID-19 on the basis of in vitro

testing and a small open-label study with significant methodological limitations 59. The clinical

study enrolled 42 patients with 26 patients receiving hydroxychloroquine compared to 16

controls. Only 36 patients were included the analysis, as 6 (23%) of the hydroxychloroquine

treated patients were lost to follow-up 59. The study authors concluded that hydroxychloroquine

had a significant effect and led to rapid SARS-CoV-2 clearance 59. This conclusion appears

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overstated based upon the study design and results, and we believe further studies of

hydroxychloroquine, including its impact on ACovCS, are required 60.

Antiviral therapies may have a role in the treatment of ACovCS. The use of

lopinavir/ritonavir for severe COVID-19 was tested prospectively in 199 patients, but

unfortunately did not lead to a significant reduction in viral-load or symptomatic improvement 57.

Remdesivir has also been proposed as an anti-viral therapy after originally being developed for

Ebola and the Marburg virus. Subsequent investigation demonstrated significant reduction of

viral replication and symptoms in a mouse model infected with SARS-CoV-1 61. Additional in

vitro testing of a human cell line demonstrated markedly reduced SARS-CoV-2 activity 62. This

led to compassionate use of remdesivir in COVID-19 patients, an effort which was eventually

suspended with initiation of currently enrolling prospective clinical trials 62. Both

hydroxychloroquine and antiviral therapies may increase the risk for torsades de pointes via QTc Downloaded from http://ahajournals.org by on April 17, 2020 prolongation 63. This risk may be increased in ACovCS if there are abnormalities of cardiac

structure or function (e.g. left ventricular hypertrophy or reduced ejection fraction), concomitant

ventricular arrhythmias or a prolonged QT interval at baseline.

Immunosuppression for myocardial injury in ACovCS has been proposed as a treatment

option; however, prior experiences with broad immunosuppression for acute myocarditis

historically have not been favorable. In the Myocarditis Treatment Trial, no significant

difference was seen in LVEF or survival between those treated with cyclosporine/prednisone,

azathioprine/prednisone or placebo in patients with myocarditis in the pre-COVID era 64. While

there were several limitations of the trial, these results do not support widespread use of

immunosuppressive therapies for myocarditis. A systematic Cochrane review evaluated the

efficacy of steroids for acute viral myocarditis in 8 randomized controlled trials with a total of

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719 patients in the pre-COVID era. They concluded that glucocorticoid therapy did not reduce

the composite end-point of mortality or heart transplant 65. Steroid use in severe COVID-19

appears common in reports, and use is numerically higher in non-survivors, although that

observation is likely confounded by indication for steroid initiation 16. Given the concern that

steroids may prolong SARS-COV-2 viral persistence, corticosteroid treatment should not be

routine, but rather may be considered salvage therapy with multidisciplinary input in select cases

with hemodynamically unstable patients 58.

As discussed above, cytokine activation appears to be a prominent feature of severe

COVID-19 illness and ACovCS with marked elevations of IL-6 and other inflammatory markers.

Sarilumab, siltuximab and tocilizumab are IL-6 inhibitors that have potential utility in ACovCS

and severe COVID-19 66. Tocilizumab is FDA-approved to manage cytokine release syndrome

due to CAR-T cell therapy and is being investigated for pneumonitis induced by immune Downloaded from http://ahajournals.org by on April 17, 2020 checkpoint inhibitors 21, 67. Trials with sarilumab, siltuximab and tocilizumab are underway in

patients with COVID-19, and will provide additional information on therapeutic efficacy and

safety and impact on ACovCS 68-70. In the interim, these agents can be considered for

compassionate use on a case-by-case basis with multidisciplinary input.

Given the known association between myocarditis and auto-antibodies, intravenous

immunoglobulin (IVIG) is theorized as a possible treatment for viral-associated myocarditis.

However, in a well conducted study in the pre-COVID era, IVIG did not improve LVEF or

event-free survival at 1-year follow-up 71. This study highlighted the lack of high-quality

evidence for the routine use of IVIG to treat with idiopathic dilated cardiomyopathy or

myocarditis, although the treatment appeared safe. Use of 1 g/kg IVIG daily for two days can be

considered in select cases for hemodynamically unstable patients due to suspected fulminant

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myocarditis as salvage therapy with multidisciplinary input. However, it is important to note this

is an extremely limited resource and should be reserved for patients with high clinical suspicion

of cardiomyopathy due to myocarditis rather than cytokine storm or stress-induced

cardiomyopathy.

More focused antibody therapy using convalescent plasma from recovered COVID-19

patients has been approved recently by the Food and Drug Administration 72. A recent report

described treatment of 5 critically ill patients with convalescent plasma containing a SARS-CoV-

2– specific antibody (IgG) obtained from COVID-19 survivors 73. In this uncontrolled case

series, they reported an improved clinical status, an observation which merits further clinical

investigation.

If myocardial injury is diagnosed clinically and the patient recovers from COVID-19,

similar to historical expert opinion recommendations for non-COVID myocarditis, abstinence Downloaded from http://ahajournals.org by on April 17, 2020 from competitive sports or aerobic activity would be reasonable for a period of 3-6 months until

resolution of myocardial inflammation by cardiac MRI and/or normalization of troponin 74. This

recommendation is based on experimental animal models and several retrospective observational

studies 74-76. The initiation of guideline-directed medical therapy (GDMT) may be considered for

all patients with suspected myocarditis and reduced systolic function in accordance with the most

recent guidelines for the management of heart failure after a period of clinical stability and

improvement such that individuals are preparing for discharge 77. We advise delaying GDMT

until that later time point given that respiratory status can deteriorate rapidly earlier in the illness

and require intubation leading to hypotension.

Finally, in select cases with refractory shock or ventricular arrhythmias due to ACovCS,

mechanical support can be considered if available at the treating facility. Case reports have

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described successful rescue of patients with cardiogenic shock with use of veno-arterial (VA),

and veno-arterial-veno (V-A-V) ECMO 5, 12, 19. If cardiogenic shock is suspected secondary to

myocarditis, expert consultation with an advanced heart failure team should be strongly

considered.

Summary

In conclusion, COVID-19 is associated with the development of an associated cardiovascular

syndrome including acute myocardial injury, arrhythmias, and cardiomyopathy that we have

termed Acute COVID-19 Cardiovascular Syndrome (ACovCS). It is uncertain to what extent the

acute systolic heart failure is mediated by myocarditis, cytokine storm, microvascular

dysfunction, small vessel thrombotic complications, or a variant of stress-induced

cardiomyopathy. Patients with elevated troponin who are otherwise clinically stable do not

require extensive cardiac imaging during the acute phase of COVID-19 if point of care cardiac Downloaded from http://ahajournals.org by on April 17, 2020 ultrasound is not available. Patients with hemodynamic instability or ventricular arrhythmias

require more detailed evaluation, cardiology consultation and consideration for enrollment in

clinical trials or experimental therapies.

Acknowledgements: None

Sources of Funding: None

Disclosures: NH, MD and LC report no relevant conflicts of interest or disclosures. BB has

received consulting fees from Bristol Myers Squibb, scPharmaceuticals, Baxter Healthcare

Corporation , Sanofi-Aventis, Relypsa; and serves on the Clinical Event Committee for GUIDE

10.1161/CIRCULATIONAHA.120.047349

HF Trial sponsored by Abbott Vascular, and Data Safety Monitoring Committee of ANTHEM

trial (Autonomic REGULATION Therapy to Enhance Myocardial Function and Reduce

progression of Heart Failure with reduced ejection fraction) sponsored by Liva Nova.

Downloaded from http://ahajournals.org by on April 17, 2020

10.1161/CIRCULATIONAHA.120.047349

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Table 1. Spectrum of Acute COVID-19 Cardiovascular Syndrome (ACovCS)

Spectrum of Acute COVID-19 Cardiovascular Syndrome (ACovCS)

Acute Coronary Syndrome Chest Pain, Elevated Troponin, Wall Motion Abnormalities and/or (STEMI or NSTEMI)* ST-depression or Elevation ± T-wave abnormalities.

Acute Myocardial Injury Troponin Elevated ± Additional Symptoms. without Obstructive CAD†

Atrial Arrhythmias, Ventricular Tachycardia, Ventricular Arrhythmias Fibrillation, and/or Complete Heart Block**.

De novo Systolic Dysfunction Myocarditis or Myopericarditis Cytokine mediated Cardiomyopathy Stress-induced Cardiomyopathy Heart Failure ± Mediated via other risk factors (e.g., atrial arrhythmias) Cardiogenic Shock Acute on Chronic Decompensated Systolic Dysfunction ± Elevated troponin Recurrent Systolic Dysfunction after LVEF Recovery Downloaded from http://ahajournals.org by on April 17, 2020 Heart Failure with Preserved LVEF (HFpEF) ‡

Pericardial Effusion ± Tamponade

Thromboembolic Arterial Thromboembolism, Deep Vein Thrombosis, Intracardiac Thrombus, Microvascular Thrombi**, Pulmonary Embolism,

Complications Stroke * Reported with obstructive, non-obstructive, or no coronary artery disease. † It is uncertain if an abnormal troponin is required prior to onset of ACovCS. Additionally, patients are reported to have either non-obstructive or no epicardial coronary artery disease. ‡ Unknown at this time whether Heart Failure with Preserved LVEF is part of this spectrum. ** Although these complications may be anticipated with our incomplete understanding of COVID-19, to our knowledge reports of heart block or cardiac microvascular thrombi have not been published to date. Abbreviations: CAD, coronary artery disease; LVEF, left ventricular systolic dysfunction; NSTEMI, non- ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

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Figure Legends

Figure 1. Spectrum of the Acute COVID-19 Cardiovascular Syndrome

The spectrum of the Acute COVID-19 Cardiovascular Syndrome (ACovCS) encompasses a

variety of cardiovascular syndromes described for patients presenting with COVID-19. Reports

of pericardial effusions and cardiac tamponade in patients with COVID-19 have been published.

Although the prevalence of pericardial effusion in ACovCS remains uncertain, significant

effusions do not appear to be common. Clinical images are representative of the proposed

ACovCS disease spectrum and several, but not all images are from patients with ACovCS.

a Reported with obstructive, non-obstructive, or no coronary artery disease.

b It is uncertain if an abnormal troponin is required prior to onset of ACovCS and patients are

reported to have either non-obstructive or no epicardial coronary artery disease. Downloaded from http://ahajournals.org by on April 17, 2020 c Significant uncertainty remains regarding the etiology and prevalence of the acute myocardial

injury for patients without obstructive CAD and COVID-19. While myocarditis, cytokine storm,

or stress cardiomyopathy are leading considerations, additional potential etiologies include

hypoxemia and microvascular dysfunction from small vessel thrombosis.

Abbreviations: ACovCS, Acute COVID-19 Cardiovascular Syndrome; CAD, coronary artery

disease; COVID-19, Coronavirus Disease 2019; NSTEMI, non-ST-elevation myocardial

infarction; STEMI, ST-elevation myocardial infarction.

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Figure 2. Potential Mechanisms of Myocardial Injury in Acute COVID-19 Cardiovascular

Syndrome

Multiple mechanisms have the potential to result in non-ischemic myocardial injury in COVID-

19. a Myocardial injury defined as cardiac troponin value >99th percentile of the upper reference

limit. Abbreviations: CV, cardiovascular; COVID-19, Coronavirus Disease 2019.

Figure 3. SARS-CoV-2 Host Cell Entry

A - Simplified mechanism of SARS-CoV-2 viral entry to host cells. The SARS-CoV-2 virus

expresses spike proteins with an S1 subunit that binds to ACE2 expressed on host cells. B –

After binding to host ACE2, the host serine protease TMPRSS2 performs critical protein priming

which leads to conformational changes, viral cell entry and cell infection. C – Antibodies to the

S1 subunit of the spike protein, ACE2 and TMPRSS2 are potential therapeutic targets which Downloaded from http://ahajournals.org by on April 17, 2020 reduce viral infectivity. Abbreviations: ACE2, angiotensin-converting enzyme 2; SARS-CoV-2,

Severe Acute Respiratory Syndrome Coronavirus 2; Transmembrane serine protease 2,

TMPRSS2.

Figure 4. Proposed Assessment and Management of ACovCS with Acute Myocardial

Injury

Proposed Assessment and Management of ACovCS with Acute Myocardial Injury

a If the treating clinician has the ability to provide a point of care cardiac ultrasonography

without increasing COVID-19 exposure or personal protective gear use, limited LVEF

assessment can be considered as a depressed systolic function would identify higher-risk

patients.

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b Repeat troponin testing is indicated with a deterioration of clinical status.

c This pathway attempts to balance the imperfect trade-offs of increased diagnostic uncertainty

without compromising patient outcomes while minimizing unnecessary staff exposures and

testing that will not immediately change clinical care.

d The 2015 Eligibility and Disqualification Recommendations for Competitive Athletes With

Cardiovascular Abnormalities task recommends abstinence from competitive sports or aerobic

activity for a period of 3-6 months until resolution of myocardial inflammation.

e Assessment of the left ventricular ejection fraction should be considered at early follow-up for

patients with an abnormal troponin during hospitalization to either identify patients with reduced

systolic function or to complete a full cardiac assessment. Complete assessment should occur

once a patient is no longer considered infectious in accordance with Center for Disease Control Downloaded from http://ahajournals.org by on April 17, 2020 recommendations for the discontinuation of transmission-based precautions for patients with

COVID-19.

f There are currently no evidence-based therapies for COVID-19 with robust clinical evidence of

efficacy. Enrollment into a clinical trial should be strongly considered if available at the treating

center. Additional treatment with anti-viral, anti-cytokine and additional investigational drugs

should be completed on a case-by-case basis after consultation with a multidisciplinary team.

g Consideration of pulmonary arterial catheters, inotropic and/or mechanical support (i.e. intra-

aortic balloon pump, temporary left ventricular support device, VA-ECMO) should be completed

on a case-by-case basis taking into account patient characteristics, availability of appropriately

trained staff and the ability of the healthcare institution to safely manage a support device.

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h Evidence of acute myocarditis by imaging or biopsy within myocardial tissue may modify the

choice and dosing regimen of therapies.

Abbreviations: ACovCS, Acute COVID-19 Cardiovascular Syndrome; COVID-19; Coronavirus

Disease 2019; CT, computed tomography; LVEF, left ventricular ejection fraction; MRI,

magnetic resonance imaging; PA, pulmonary artery; VA-ECMO, venoarterial extracorporeal

membrane oxygenation; VF, ventricular fibrillation; VT, ventricular tachycardia.

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Downloaded from http://ahajournals.org by on April 17, 2020 Downloaded from http://ahajournals.org by on April 17, 2020